5.2.4. Cryptorchidism

The mechanism underlying infertility in males with a history of cryptorchidism is not well understood. Men with bilateral cryptorchidism have a higher risk of infertility compared with those who have unilateral cryptorchidism [38,39,123]. Additionally, age at orchidopexy also affects sperm production and future fertility [40]. It is estimated that greater than 50% of men with a history of cryptorchidism will have varying degrees of spermatogenic failure and may require surgical sperm retrieval to conceive biological children [39,123].

Men who have had prior orchidopexy typically have substantial peri-testicular scar, no tunica vaginalis, and often have an abnormal lie or position of the testis with an anterior epididymis. Surgical treatment in these men also often reveals an atypical blood supply to the testis with variable patterns of vessels on the tunica albuginea. Within the testis, most tubules are typically sclerotic with distinctively different tubules containing isolated foci of spermatogenesis visible during microdissection. Studies examining ICSI outcomes solely in men with a history of cryptorchidism report SRR ranging from 52 to 85%, pregnancy rates ranging from 10–46%, LBR ranging from 33–100%, and miscarriage rates ranging from 6.3–8.1% (Tables 2 and 3) [41–45]. Patients with cryptorchidism have a wide range of fertility potential and more studies of these individuals is needed to determine the mechanisms underlying their infertility so that patients can be counseled with accurate prognostic information.

#### *5.3. Sperm Effects on ICSI Outcomes*

For men with severely impaired sperm production, embryo development appears to be adversely affected by the (testicular) source of sperm and level of sperm production with decreased development associated with higher FSH levels [124,125]. Men with NOA often have such low fertilization rates that a limited number of embryos exist on day 3. Therefore, transfer of day 3 embryos is routinely required, as further in vitro culture risks losing the embryos available for transfer on day 3. Of note, high-quality day 3 embryos have been suggested in some studies to be equivalent to day 5 blastocysts in terms of pregnancy and live birth rate [124]. However, existing data are limited with no interpretable data on embryo morphokinetic parameters, although some publications sugges<sup>t</sup> that embryo development may be less efficient in me with lower sperm production [124,126]. Similarly, there are limited published data on blastocyst euploidy rates. Given the frequency of day 3 embryo transfer for couples where men have NOA, data obtained from the select group with blastocysts available for transfer may not reflect results that are generalizable for NOA patients as a whole.

Advances in the understanding of sperm biology have revealed important paternal effects on embryo development and quality. Poor semen parameters have been demonstrated to negatively affect blastocyst formation rates after IVF and ICSI [124,126–129]. Ejaculated sperm has been found to produce higher fertilization and pregnancy rates than testicular sperm [130]. Additionally, when compared to men with obstructive azoospermia undergoing ICSI, men with NOA undergoing ICSI have lower rates of fertilization, blastocyst formation, implantation, and pregnancy [124,126,131,132].

#### **6. Improving ICSI Outcomes from the Male Perspective**

Optimization of hormone levels in NOA men may improve SRR [71]. Increased numbers of sperm may allow selection of more optimal sperm to be used for ICSI. Currently, various methods exist for improving sperm selection, including viability assays, cell sorting methods and enhanced microscopic analysis for selection of sperm for ICSI, although manual selection of individual sperm is the most common approach used in men with NOA [133].

Conventional sperm selection methods including the swim-up method, migration density, and density gradients rely heavily on the motility of sperm, and cannot be used for sperm retrieved from the testis as certain maturation processes have not occurred in testicular sperm and these sperm are immotile. Magnetic activated cell sorting (MACS) is a method of sperm selection using annexin V-conjugated magnetic beads to isolate viable sperm. A systematic review analyzing five prospective, randomized trials evaluating MACS compared to standard sperm selection methods (including swim-up and density gradient methods) found significantly increased pregnancy rates resulted after MACS [134]. Intracytoplasmic morphologically selected sperm injection (IMSI) is the process of selecting sperm at x6,600 magnification to examine motile sperm organellar morphology [133]. A prospective, randomized study examining ICSI and IMSI in couples with severe male factor infertility reported higher CPR with IMSI (39.2% IMSI vs. 26.5% ICSI, *p* = 0.004) [135]. This study along with other studies, including one meta-analysis, also demonstrated a decreased miscarriage rate and improved implantation rates with IMSI compared with ICSI [133,135]. However, a recent Cochrane review of the efficacy of IMSI compared with traditional ICSI did not provide any conclusive evidence to sugges<sup>t</sup> that IMSI is superior to ICSI in terms of clinical outcomes (CPR, LBR) [136].

Additional work on novel techniques is underway that will further optimize the sperm chosen for oocyte injection. One promising technique is microfluidic sorting of sperm, which allows for analysis of sperm count, motility, and morphology on a microscopic level, allowing for the identification and selection of sperm with the best qualities [137,138]. Studies examining microfluidics-sorted sperm have demonstrated improved ICSI and clinical outcomes compared to sperm selected by conventional methods [138,139]. However, further work is needed to fully develop this technology for mainstream use [140]. Given the limited numbers of sperm available for retrieval from men with NOA, it is more challenging to apply sperm selection techniques that could be used for sperm samples from men with oligozoospermia.
